dbSNP rs201145362: POU2F3:p.Ala149Glu (chr11-120305031-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014352.4(POU2F3):c.446C>A(p.Ala149Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,451,032 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A149V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

POU2F3
NM_014352.4 missense, splice_region

Scores

Splicing: ADA: 0.9941

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.78

Variant links:

Genes affected

POU2F3 (HGNC:19864): (POU class 2 homeobox 3) This gene encodes a member of the POU domain family of transcription factors. POU domain transcription factors bind to a specific octamer DNA motif and regulate cell type-specific differentiation pathways. The encoded protein is primarily expressed in the epidermis, and plays a critical role in keratinocyte proliferation and differentiation. The encoded protein is also a candidate tumor suppressor protein, and aberrant promoter methylation of this gene may play a role in cervical cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

POU2F3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU2F3	NM_014352.4 link	c.446C>A	p.Ala149Glu	missense_variant, splice_region_variant	Exon 7 of 13	ENST00000543440.7	NP_055167.2	Q9UKI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POU2F3	ENST00000543440.7 link	c.446C>A	p.Ala149Glu	missense_variant, splice_region_variant	Exon 7 of 13	1	NM_014352.4	ENSP00000441687.2	Q9UKI9-1
POU2F3	ENST00000533620.5 link	n.*112C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 14	1		ENSP00000435738.2	E9PIN6
POU2F3	ENST00000533620.5 link	n.*112C>A		3_prime_UTR_variant	Exon 8 of 14	1		ENSP00000435738.2	E9PIN6
POU2F3	ENST00000260264.8 link	c.452C>A	p.Ala151Glu	missense_variant, splice_region_variant	Exon 7 of 13	2		ENSP00000260264.4	Q9UKI9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451032

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

-0.019

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.68

REVEL

Uncertain

0.41

Sift4G

Uncertain

0.025

D;D

Polyphen

0.92

.;P

Vest4

0.73

MutPred

0.26

.;Gain of solvent accessibility (P = 0.026);

MVP

0.79

MPC

0.86

ClinPred

0.99

GERP RS

6.2

Varity_R

0.43

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over